EP1732523B9 - Kaliumbindende polymere und ihre verwendungen - Google Patents
Kaliumbindende polymere und ihre verwendungen Download PDFInfo
- Publication number
- EP1732523B9 EP1732523B9 EP05732849A EP05732849A EP1732523B9 EP 1732523 B9 EP1732523 B9 EP 1732523B9 EP 05732849 A EP05732849 A EP 05732849A EP 05732849 A EP05732849 A EP 05732849A EP 1732523 B9 EP1732523 B9 EP 1732523B9
- Authority
- EP
- European Patent Office
- Prior art keywords
- shell
- polymer
- potassium
- binding
- core
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 229920000642 polymer Polymers 0.000 title claims description 186
- 230000027455 binding Effects 0.000 title claims description 135
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 title claims description 121
- 229910052700 potassium Inorganic materials 0.000 title claims description 121
- 239000011591 potassium Substances 0.000 title claims description 121
- 229920002873 Polyethylenimine Polymers 0.000 claims description 54
- -1 epichlorohydrine Chemical class 0.000 claims description 33
- 208000002682 Hyperkalemia Diseases 0.000 claims description 32
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 claims description 31
- 239000008194 pharmaceutical composition Substances 0.000 claims description 30
- TYCFGHUTYSLISP-UHFFFAOYSA-N 2-fluoroprop-2-enoic acid Chemical compound OC(=O)C(F)=C TYCFGHUTYSLISP-UHFFFAOYSA-N 0.000 claims description 25
- 239000002253 acid Substances 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 19
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 17
- 229940079593 drug Drugs 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 15
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims description 11
- 239000000306 component Substances 0.000 claims description 11
- 239000008358 core component Substances 0.000 claims description 11
- 150000001412 amines Chemical class 0.000 claims description 9
- 229920001577 copolymer Polymers 0.000 claims description 9
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 claims description 8
- 150000004820 halides Chemical group 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 239000005541 ACE inhibitor Substances 0.000 claims description 7
- 229920001661 Chitosan Polymers 0.000 claims description 7
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 7
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 7
- 239000012039 electrophile Substances 0.000 claims description 7
- 229920000669 heparin Polymers 0.000 claims description 7
- 229960002897 heparin Drugs 0.000 claims description 7
- 239000003286 potassium sparing diuretic agent Substances 0.000 claims description 7
- 229940097241 potassium-sparing diuretic Drugs 0.000 claims description 7
- 150000008064 anhydrides Chemical class 0.000 claims description 6
- 150000004982 aromatic amines Chemical class 0.000 claims description 6
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 6
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 6
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 claims description 6
- 229960001082 trimethoprim Drugs 0.000 claims description 6
- JUVWKFKXIVLAHQ-UPHRSURJSA-N (z)-2,3-difluorobut-2-enedioic acid Chemical compound OC(=O)C(\F)=C(\F)C(O)=O JUVWKFKXIVLAHQ-UPHRSURJSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 239000012948 isocyanate Substances 0.000 claims description 5
- 150000002513 isocyanates Chemical class 0.000 claims description 5
- 150000002924 oxiranes Chemical class 0.000 claims description 5
- SOBDFTUDYRPGJY-UHFFFAOYSA-N 1,3-bis(ethenylsulfonyl)propan-2-ol Chemical compound C=CS(=O)(=O)CC(O)CS(=O)(=O)C=C SOBDFTUDYRPGJY-UHFFFAOYSA-N 0.000 claims description 4
- OZDGMOYKSFPLSE-UHFFFAOYSA-N 2-Methylaziridine Chemical compound CC1CN1 OZDGMOYKSFPLSE-UHFFFAOYSA-N 0.000 claims description 4
- QWZOJDWOQYTACD-UHFFFAOYSA-N 2-ethenylsulfonyl-n-[2-[(2-ethenylsulfonylacetyl)amino]ethyl]acetamide Chemical compound C=CS(=O)(=O)CC(=O)NCCNC(=O)CS(=O)(=O)C=C QWZOJDWOQYTACD-UHFFFAOYSA-N 0.000 claims description 4
- KGIGUEBEKRSTEW-UHFFFAOYSA-N 2-vinylpyridine Chemical compound C=CC1=CC=CC=N1 KGIGUEBEKRSTEW-UHFFFAOYSA-N 0.000 claims description 4
- RDAFNSMYPSHCBK-UHFFFAOYSA-N 3-phenylprop-2-en-1-amine Chemical compound NCC=CC1=CC=CC=C1 RDAFNSMYPSHCBK-UHFFFAOYSA-N 0.000 claims description 4
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 4
- 150000001350 alkyl halides Chemical class 0.000 claims description 4
- 239000002333 angiotensin II receptor antagonist Substances 0.000 claims description 4
- 229940125364 angiotensin receptor blocker Drugs 0.000 claims description 4
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- UYMKPFRHYYNDTL-UHFFFAOYSA-N ethenamine Chemical compound NC=C UYMKPFRHYYNDTL-UHFFFAOYSA-N 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- ZIUHHBKFKCYYJD-UHFFFAOYSA-N n,n'-methylenebisacrylamide Chemical compound C=CC(=O)NCNC(=O)C=C ZIUHHBKFKCYYJD-UHFFFAOYSA-N 0.000 claims description 4
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- IQIJRJNHZYUQSD-UHFFFAOYSA-N ethenyl(phenyl)diazene Chemical compound C=CN=NC1=CC=CC=C1 IQIJRJNHZYUQSD-UHFFFAOYSA-N 0.000 claims description 3
- 125000001033 ether group Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- VXDHQYLFEYUMFY-UHFFFAOYSA-N 2-methylprop-2-en-1-amine Chemical compound CC(=C)CN VXDHQYLFEYUMFY-UHFFFAOYSA-N 0.000 claims description 2
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 2
- 150000005690 diesters Chemical class 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 229920001289 polyvinyl ether Polymers 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims 1
- 239000011257 shell material Substances 0.000 description 122
- 239000000203 mixture Substances 0.000 description 112
- 238000000034 method Methods 0.000 description 83
- 150000001768 cations Chemical class 0.000 description 82
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 78
- 239000011324 bead Substances 0.000 description 76
- ZYMKZMDQUPCXRP-UHFFFAOYSA-N fluoro prop-2-enoate Chemical compound FOC(=O)C=C ZYMKZMDQUPCXRP-UHFFFAOYSA-N 0.000 description 69
- 239000000243 solution Substances 0.000 description 65
- 239000011162 core material Substances 0.000 description 58
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
- 239000012528 membrane Substances 0.000 description 50
- 239000000499 gel Substances 0.000 description 43
- 239000011258 core-shell material Substances 0.000 description 41
- 239000002245 particle Substances 0.000 description 40
- 229920005989 resin Polymers 0.000 description 37
- 239000011347 resin Substances 0.000 description 37
- 230000035699 permeability Effects 0.000 description 35
- 239000000178 monomer Substances 0.000 description 29
- 238000000576 coating method Methods 0.000 description 27
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 26
- 239000002904 solvent Substances 0.000 description 25
- 230000008569 process Effects 0.000 description 24
- 239000011248 coating agent Substances 0.000 description 23
- 230000015572 biosynthetic process Effects 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- 239000000463 material Substances 0.000 description 21
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 18
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 18
- 239000000284 extract Substances 0.000 description 18
- ZTZJVAOTIOAZGZ-UHFFFAOYSA-N methyl 2-fluoroacrylate Chemical compound COC(=O)C(F)=C ZTZJVAOTIOAZGZ-UHFFFAOYSA-N 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- 238000005804 alkylation reaction Methods 0.000 description 17
- 210000001035 gastrointestinal tract Anatomy 0.000 description 17
- 239000003999 initiator Substances 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 150000002500 ions Chemical class 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 16
- 230000029936 alkylation Effects 0.000 description 15
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 14
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 241001465754 Metazoa Species 0.000 description 14
- 238000001727 in vivo Methods 0.000 description 14
- 238000004255 ion exchange chromatography Methods 0.000 description 14
- 239000011777 magnesium Substances 0.000 description 14
- 239000011734 sodium Substances 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 13
- 238000005354 coacervation Methods 0.000 description 13
- 230000003247 decreasing effect Effects 0.000 description 13
- 230000002550 fecal effect Effects 0.000 description 13
- 229910052749 magnesium Inorganic materials 0.000 description 13
- 238000006116 polymerization reaction Methods 0.000 description 13
- 239000000523 sample Substances 0.000 description 13
- 239000011780 sodium chloride Substances 0.000 description 13
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- 230000008901 benefit Effects 0.000 description 12
- 239000003613 bile acid Substances 0.000 description 12
- 239000007910 chewable tablet Substances 0.000 description 12
- 210000001072 colon Anatomy 0.000 description 12
- 210000003608 fece Anatomy 0.000 description 12
- 229910052708 sodium Inorganic materials 0.000 description 12
- 239000003826 tablet Substances 0.000 description 12
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 11
- LBSPZZSGTIBOFG-UHFFFAOYSA-N bis[2-(4,5-dihydro-1h-imidazol-2-yl)propan-2-yl]diazene;dihydrochloride Chemical compound Cl.Cl.N=1CCNC=1C(C)(C)N=NC(C)(C)C1=NCCN1 LBSPZZSGTIBOFG-UHFFFAOYSA-N 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 11
- 235000005911 diet Nutrition 0.000 description 11
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- 230000000694 effects Effects 0.000 description 11
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- 229940059939 kayexalate Drugs 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000011575 calcium Substances 0.000 description 10
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- 239000000194 fatty acid Substances 0.000 description 10
- 229930195729 fatty acid Natural products 0.000 description 10
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- 150000003839 salts Chemical class 0.000 description 10
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- 229910001414 potassium ion Inorganic materials 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 8
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- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Inorganic materials O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 8
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 7
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- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 6
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- YIVJZNGAASQVEM-UHFFFAOYSA-N Lauroyl peroxide Chemical compound CCCCCCCCCCCC(=O)OOC(=O)CCCCCCCCCCC YIVJZNGAASQVEM-UHFFFAOYSA-N 0.000 description 6
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
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- 125000002091 cationic group Chemical group 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
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Images
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- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F120/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
- C08F120/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
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- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F128/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a bond to sulfur or by a heterocyclic ring containing sulfur
- C08F128/02—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a bond to sulfur or by a heterocyclic ring containing sulfur by a bond to sulfur
Definitions
- Hyperkalemia is rare in the general population of healthy individuals. However, certain groups definitely exhibit a higher incidence of hyperkalemia. In patients who are hospitalized, the incidence of hyperkalemia ranges from about 1-10%, dependng on the definition of hyperkalemia. Patients at the extremes of life, either premature or elderly, are at high risk. The presence of decreased renal function, genitourinary disease, cancer, severe diabetes, and polypharmacy can also predispose patients to hyperkalemia.
- Figure 10 depicts potassium and magnesium binding by Dowex beads coated with benzylated polyethyleneimine.
- the present invention provides, polymeric pharmaceutical compositions the use thereof and kits for the treatment of animal subjects.
- animal subject and “animal” as used herein includes humans as well as other mammals.
- the present invention provides polymeric compositions for the removal of potassium ions.
- these compositions are used for the removal of potassium ions from the gastrointestinal tract of animal subjects.
- the capacity of the potassium binding polymers can also be determined in vitro . It is preferred that the in vitro potassium binding capacity is determined in conditions that mimic the physiological conditions of the gastro-intestinal tract, in particular the colon. In some embodiments, the in vitro potassium binding capacity is determined in solutions with a pH of about 5.5 or more. In various embodiments, in vitro potassium binding capacity in a pH of about 5.5 or more is equal to or more than 6 mmol per gm of polymer. A preferred range of in vitro potassium binding capacity in a pH of about 5.5 or more is about 6 mmol to about 12 mmol per gm of polymer.
- the in vitro potassium binding capacity in a pH of about 5.5 or more is equal to about 6 mmol or more per gm, more preferred is about 8 mmol or more per gm, even more preferred is about 10 mmol or more per gm, and most preferred is about 12 mmol or more per gm.
- the period of retention is preferred to be during the time that the composition is being used therapeutically and/or prophylactically.
- the retention period is the time of residence of the composition in the gastro-intestinal tract and more particularly the average residence time in the colon.
- the potassium binding polymer is not Kayexalate, sodium polystyrene sulfonate, or an ammonium form of polystyrene sulfonate.
- the shell material may be engineered to impose a lower permeability to higher valency cations.
- the permeability of the shell to alkaline-earth cations is altered by changing the average pore size, charge density and hydrophobicity of the membrane.
- Mg ++ and Ca ++ hydrated ions have a large size compared with monovalent cations such as K + and Na + as indicated below in Table 5 ( Nightingale E.R., J. Phys. Chem., 63, (1959), 1381-89 ). TABLE 5 Metal ions Hydrated radii (angstroms) K + 3.31 NH 4 + 3.31 Na + 3.58 Mg ++ 4.28 Ca 2+ 4.12
- alkylating agents include a C3 -C20 alkyl halide (e.g., an n-butyl halide, n-hexyl halide, n-octyl halide, n-decyl halide, n-dodecyl halide, n-tetradecyl halide, n-octadecyl halide, and combinations thereof); a C1 -C20 hydroxyalkyl halide (e.g., an 11-halo-1-undecanol); a C1 -C20 aralkyl halide (e.g., a benzyl halide); a C1 -C20 alkyl halide ammonium salt (e.g., a (4-halobutyl) trimethylammonium salt, (6-halohexyl)trimethylammonium salt, (8-halooctyl)trimethylam
- Core-shell polymerizations can be emulsion polymerization, suspension/miniemulsion polymerization, or dispersion polymerization. All these processes employ free radical polymerizations.
- emulsion polymerization the polymerization takes place in aqueous medium with a surfactant, monomer with a low water solubility, and a water soluble free radical initiator.
- Polymer particles are formed by micellar or homogeneous nucleation or both.
- Core shell particles can be formed theoretically by feeding the core monomer first and the shell monomer second as long as the monomer is spontaneously consumed as it is fed (“starved regime").
- the potassium binding core beads are preferably made from a water insoluble monomer (e.g. alkylester of a-fluoro-acrylic acid).
- the potassium binding polymers described herein are administered chronically.
- such chronic treatments will enable patients to continue using drugs that cause hyperkalemia, such as potassium-sparing diuretics, ACEI's, non-steroidal anti-inflammatory drugs, heparin, or trimethoprim.
- drugs that cause hyperkalemia such as potassium-sparing diuretics, ACEI's, non-steroidal anti-inflammatory drugs, heparin, or trimethoprim.
- use of the polymeric compositions described herein will enable certain patient populations, who were unable to use hyperkalemia causing drugs, to use such drugs.
- the compounds may be formulated as a sustained release preparation. Numerous techniques for formulating sustained release preparations are known in the art.
- compositions of the invention may be provided as pharmaceutical compositions in the form of chewable tablets.
- excipients are commonly used: a sweetening agent to provide the necessary palatability, plus a binder where the former is inadequate in providing sufficient tablet hardness; a lubricant to minimize frictional effects at the die wall and facilitate tablet ejection; and, in some formulations a small amount of a disintegrant is added to facilitate mastication.
- a sweetening agent to provide the necessary palatability, plus a binder where the former is inadequate in providing sufficient tablet hardness
- a lubricant to minimize frictional effects at the die wall and facilitate tablet ejection
- a small amount of a disintegrant is added to facilitate mastication.
- sweetening agents make up the bulk of the inactive ingredients.
- additives may include plasticizers, pigments, talc, and the like.
- plasticizers such additives and other suitable ingredients are well-known in the art; see, e.g., Gennaro AR (ed), Remington's Pharmaceutical Sciences, 20th Editi on.
- PVAm.HCl Polyvinylamine hydrochloride
- the potassium binding was calculated from actual magnesium uptake and overall binding capacity of polymer which was 5.74 meq/gm. The results are shown in Figure 10 . Increasing the ratio of shell/core caused a decrease in magnesium binding which indicates an increase in potassium binding.
- Figure 11 shows the results of the binding experiments. Controlled precipitation method for 40% benzylated PEI shows better coating and this combination of coating method and materials gives higher binding selectivity.
- the amount of each cation (in mEq) bound per gram of H + -form polymer was calculated based on the dietary intake of polymer and the difference between the amount of cation in the feces of control animals versus the amount of cation in the feces of test animals on diets containing 2% test articles.
- the calculated in vivo binding capacities for Kayexalate and FAA polymer-NH 4 + -form are shown in Table 19.
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- Diabetes (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Obesity (AREA)
- Polymers & Plastics (AREA)
- Toxicology (AREA)
- Gastroenterology & Hepatology (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Claims (14)
- Pharmazeutische Formulierung enthaltend einen oder mehrere pharmazeutisch akzeptable Trägerstoffe, Trägersubstanzen und/oder Hilfsmittel und- ein Kalium bindendes Polymer umfassend Säuregruppen ausgewählt aus der Gruppe bestehend aus Sulfonat (-SO3-), Sulfat- (-OSO3-), Carboxylat (-CO2-), Phosphonat- (-PO3-), Phosphat (-(OPO3-) und Sulfamat (-NHSO3-) und- einen elektronenabziehenden Substituenten, angeordnet neben der Säuregruppe, wobei der elektronenabziehende Substituent ausgesucht ist aus der Gruppe bestehend aus einer Hydroxylgruppe, eine Ethergruppe, eine Estergruppe und einen Halogenidatom und- worin der elektronenabziehende Substituent Fluorid ist, wenn die Säuregruppe Carboxylat ist.
- Pharmazeutische Formulierung nach Anspruch 1, worin das Polymer eine Poiyfluoracrylsäure, eine Pvlydifluormaleinsäure oder eine Kombination daraus ist.
- Pharmazeutische Formulierung nach Anspruch 1 bis 2, worin das Polymer ein 2-Fluoracrylsäure-Polymer ist, das vernetzt ist mit Divinylbenzen, Ethylenbisacrylamid, N,N'-Bis(vinylsulfonylacetyl)-ethylendiamin, 1,3-Bis(vinylsulfonyl)-2-propanol, Vinylsulfon, N,N'-Methylenbisacrylamid-polyvinylether, Polyallylether oder einer Kombination daraus.
- Pharmazeutische Formulierung nach einem der Ansprüche 1 bis 3, umfassend das Kalium bindende Polymer als Kernkomponente und außerdem umfassend eine Hüllkomponente.
- Pharmazeutische Formulierung nach Anspruch 4, worin die Hülle Copolymere umfasst und worin mindestens eine Wiederholungseinheit des Copolymers ein Vinylamin, Ethylenimin, Propylenimin, Allylamin, Methallylamin, Vinylpyridin, Alkyaminoalkyl(meth)acrylat, Alkyaminoalkyl(meth)acrylamid, Aminomethylstyrol, Chitosan oder ein Addukt eines aliphatischen oder aromatischen Amins mit mindestens einem Elektrophil, ausgewählt aus einem Epichlorhydrin, einem Alkylhalogenid und einem Epoxid, wobei das Amin gegebenenfalls in einer quarternisierten Form vorliegt, ist.
- Pharmazeutische Formulierung nach einem der Ansprüche 4 bis 5, worin die Hülle vernetzt ist durch Epoxide, Halogenide, Ester, Isocyanate oder Anhydride wie Epichlorohydrin, Alkyldiisocyanate, Alkyldihalogenide oder Diester.
- Pharmazeutische Formulierung nach einem der Ansprüche 4 bis 6, worin die Hülle Polyethylenimin umfasst.
- Pharmazeutische Formulierung nach Anspruch 7, worin die Hülle vernetztes und/oder benzyliertes Polyethylenimin umfasst.
- Pharmazeutische Formulierung nach einem der Ansprüche 4 bis 6, worin die Hülle Polyvinylamin umfasst.
- Pharmazeutische Formulierung nach einem der Ansprüche 3 oder 4, umfassend einen Kern aus 2-Fluoracrylsäure-Polymer, das vernetzt ist mit Divinylbenzen.
- Pharmazeutische Formulierung nach Anspruch 10, zusätzlich umfassend eine Hülle aus benzyliertem Polyethylenimin oder N-Dodecylpolyethylenimin.
- Pharmazeutische Formulierung nach einem der Ansprüche 1 bis 11, zusätzlich umfassend eines oder mehrere Arzneimittel ausgewählt aus der Gruppe bestehend aus kaliumsparende Diuretika, Angiotensin-converting-Enzym-Hemmer (ACEH), Angiotensinrezeptor-Blocker (ARB), nichtsteroidale Antiphlogistika, Heparin oder Trimethoprim.
- Pharmazeutisches Kit, umfassend eine pharmazeutische Formulierung nach einem der Ansprüche 1 bis 12 und zusätzlich umfassend eines oder mehrere Arzneimittel ausgewählt aus der Gruppe bestehend aus kaliumsparende Diuretika, Angiotensin-converting-Enzym-Hemmer (ACEH), Angiotensinrezeptor-Blocker (ARB), nichtsteroidale Antiphlogistika, Heparin oder Trimethoprim.
- Verwendung einer pharmazeutischen Formulierung nach einem der Ansprüche 1 bis 12 zur Herstellung eines Medikaments zur Behandlung von Hyperkaliämie.
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP10186221A EP2269590A3 (de) | 2004-03-30 | 2005-03-30 | Ion bindede Polymere und ihre Verwendung |
EP16203827.7A EP3219312B1 (de) | 2004-03-30 | 2005-03-30 | Ionenbindende polymere und verwendungen davon |
EP10186212.6A EP2269589B1 (de) | 2004-03-30 | 2005-03-30 | Ionen bindende Polymere und ihre Verwendung |
PL10152337T PL2184059T3 (pl) | 2004-03-30 | 2005-03-30 | Polimery wiążące potas do zastosowania w terapeutycznym lub profilaktycznym sposobie leczenia hiperkalemii |
EP10152337A EP2184059B1 (de) | 2004-03-30 | 2005-03-30 | Kaliumbindende Polymere zur Verwendung in einem Verfahren zur Behandlung oder Prophylaxis von Hyperkalämie |
PL05732849T PL1732523T3 (pl) | 2004-03-30 | 2005-03-30 | Polimery wiążące potas i ich zastosowania |
EP19153950.1A EP3574896A1 (de) | 2004-03-30 | 2005-03-30 | Ionenbindende polymere und verwendungen davon |
PL10186212T PL2269589T3 (pl) | 2004-03-30 | 2005-03-30 | Polimery wiążące jony i ich zastosowania |
PL16203827T PL3219312T3 (pl) | 2004-03-30 | 2005-03-30 | Polimery wiążące jon i ich zastosowania |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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US10/814,527 US7854924B2 (en) | 2004-03-30 | 2004-03-30 | Methods and compositions for treatment of ion imbalances |
US10/814,749 US8192758B2 (en) | 2004-03-30 | 2004-03-30 | Ion binding compositions |
US10/813,872 US8282960B2 (en) | 2004-03-30 | 2004-03-30 | Ion binding compositions |
US10/965,274 US7488495B2 (en) | 2004-03-30 | 2004-10-13 | Ion binding polymers and uses thereof |
PCT/US2005/010978 WO2005097081A1 (en) | 2004-03-30 | 2005-03-30 | Ion binding polymers and uses thereof |
Related Child Applications (4)
Application Number | Title | Priority Date | Filing Date |
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EP16203827.7A Division EP3219312B1 (de) | 2004-03-30 | 2005-03-30 | Ionenbindende polymere und verwendungen davon |
EP19153950.1A Division EP3574896A1 (de) | 2004-03-30 | 2005-03-30 | Ionenbindende polymere und verwendungen davon |
EP10152337.1 Division-Into | 2010-02-01 | ||
EP10152332.2 Division-Into | 2010-02-01 |
Publications (4)
Publication Number | Publication Date |
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EP1732523A1 EP1732523A1 (de) | 2006-12-20 |
EP1732523A4 EP1732523A4 (de) | 2007-06-06 |
EP1732523B1 EP1732523B1 (de) | 2010-03-17 |
EP1732523B9 true EP1732523B9 (de) | 2010-06-02 |
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Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
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EP05747062A Not-in-force EP1732524B1 (de) | 2004-03-30 | 2005-03-30 | Verfahren und zusammensetzungen zur behandlung von ionenungleichgewicht |
EP05731099A Not-in-force EP1732516B1 (de) | 2004-03-30 | 2005-03-30 | Ionenbindende zusammensetzungen |
EP05732849A Active EP1732523B9 (de) | 2004-03-30 | 2005-03-30 | Kaliumbindende polymere und ihre verwendungen |
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Application Number | Title | Priority Date | Filing Date |
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EP05747062A Not-in-force EP1732524B1 (de) | 2004-03-30 | 2005-03-30 | Verfahren und zusammensetzungen zur behandlung von ionenungleichgewicht |
EP05731099A Not-in-force EP1732516B1 (de) | 2004-03-30 | 2005-03-30 | Ionenbindende zusammensetzungen |
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EP (3) | EP1732524B1 (de) |
JP (3) | JP4964122B2 (de) |
KR (3) | KR101153035B1 (de) |
AU (3) | AU2005231383B2 (de) |
BR (3) | BRPI0509366B8 (de) |
CA (3) | CA2558029C (de) |
DE (1) | DE112005000730B4 (de) |
GB (3) | GB2430367B (de) |
MX (1) | MXPA06011270A (de) |
PL (1) | PL1732523T3 (de) |
WO (3) | WO2005097081A1 (de) |
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